Nonmelanoma skin cancer (NMSC) is the most prevalent cancer worldwide, with over 1 million new cases diagnosed each year in the US alone. Human skin is constantly exposed to UV light causing DNA damage that contributes to skin aging and the development of skin cancer. Apoptosis is essential to eliminate damaged skin cells harboring oncogenic mutations; however, keratinocytes have evolved protective mechanisms against apoptosis. These mechanisms act to preserve cellular homeostasis and epidermal integrity but can also act as a pathway for skin cells to progress to NMSC. Mammalian target of rapamycin (mTOR) signaling is activated in the epidermis by UVB, and is known to activate cell proliferation and pro- survival signaling cascades. Studies suggest that mTOR might be a useful therapeutic target in NMSC. However, a better understanding of mTOR's role in epidermal cells in response to UVB is needed and may lead to the identification of new targets to prevent NMSC. We hypothesize that selectively inhibiting mTOR will increase the sensitivity of keratinocytes to UVB-induced apoptosis and prevent the clonal expansion of initiated cells, thus inhibiting skin tumorigenesis. The proposed experiments will use the pharmacological inhibitor rapamycin and a genetic ablation technique to block mTOR signaling in keratinocytes and will examine the in vitro and in vivo responses to UVB exposure. If our hypothesis is substantiated at the completion of this project, we will establish mTOR as a critical regulator of epidermal homeostasis and an attractive chemo preventative target in NMSC.